ZEB2 haploinsufficient Mowat-Wilson syndrome induced pluripotent stem cells show disrupted GABAergic transcriptional regulation and function.

Mowat-Wilson syndrome (MWS) is a severe neurodevelopmental disorder caused by heterozygous variants in the gene encoding transcription factor . Affected individuals present with structural brain abnormalities, speech delay and epilepsy. In mice, conditional loss of Zeb2 causes hippocampal degeneration, altered migration and differentiation of GABAergic interneurons, a heterogeneous population of mainly inhibitory neurons of importance for maintaining normal excitability.

Monoallelic and bi-allelic variants in NCDN cause neurodevelopmental delay, intellectual disability, and epilepsy.

Neurochondrin (NCDN) is a cytoplasmatic neural protein of importance for neural growth, glutamate receptor (mGluR) signaling, and synaptic plasticity. Conditional loss of Ncdn in mice neural tissue causes depressive-like behaviors, impaired spatial learning, and epileptic seizures. We report on NCDN missense variants in six affected individuals with variable degrees of developmental delay, intellectual disability (ID), and seizures.

Empty mesoporous silica particles significantly delay disease progression and extend survival in a mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is a devastating incurable neurological disorder characterized by motor neuron (MN) death and muscle dysfunction leading to mean survival time after diagnosis of only 2-5 years. A potential ALS treatment is to delay the loss of MNs and disease progression by the delivery of trophic factors. Previously, we demonstrated that implanted mesoporous silica nanoparticles (MSPs) loaded with trophic factor peptide mimetics support survival and induce differentiation of co-implanted embryonic stem cell (ESC)-derived MNs.

Generation of two human iPSC lines (UUIGPi013-A and UUIPGi014-A) from cases with Down syndrome and full trisomy for chromosome 21 (T21).

Down syndrome (DS) is caused by trisomy for chromosome 21 (T21). We generated two induced pluripotent stem cell (iPSC) lines from skin fibroblasts of two males with DS using Sendai virus delivery of OCT4, SOX2, KLF4, and c-MYC. Characterization of the two iPSC lines, UUIGPi013-A and UUIPGi014-A, showed that they are genetically stable with a 47,XY,+21 karyotype.

Aberrant splicing due to a novel RPS7 variant causes Diamond-Blackfan Anemia associated with spontaneous remission and meningocele.

Diamond-Blackfan Anemia (DBA) is a congenital pure red cell aplasia caused by heterozygous variants in ribosomal protein genes. The hematological features associated with DBA are highly variable and non-hematological abnormalities are common. We report herein on an affected mother and her daughter presenting with transfusion-dependent anemia.

Neurotrophic Effects of Vascular Endothelial Growth Factor B and Novel Mimetic Peptides on Neurons from the Central Nervous System.

Vascular endothelial growth factor B (VEGFB) is a pleiotropic trophic factor, which in contrast to the closely related VEGFA is known to have a limited effect on angiogenesis. VEGFB improves survival in various tissues including the nervous system, where the effect was observed mainly for peripheral neurons. The neurotrophic effect of VEGFB on central nervous system neurons has been less investigated.

Generation of a human Neurochondrin deficient iPSC line KICRi002-A-3 using CRISPR/Cas9.

The role of Neurochondrin (NCDN) in humans is not well understood. Mice with a conditional Ncdn knock-out show epileptic seizures, depressive-like behaviours and impaired spatial learning. Using CRISPR/Cas9, we generated a Neurochondrin deficient human iPSC line KICRi002-A-3 carrying a homozygous 752 bp deletion / 2 bp insertion in the NCDN gene.

Incontinentia pigmenti: Generation of an IKBKG deficient human iPSC line (KICRi002-A-1) on a 46,XY background using CRISPR/Cas9.

Incontinentia pigmenti (IP) is an X-linked dominant neuroectodermal dysplasia caused by loss-of-function mutations in the IKBKG gene. Using CRISPR/Cas9 technology, we generated an IKBKG knock-out iPSC line (KICRi002-A-1) on a 46,XY background. The iPSC line showed a normal karyotype, expressed pluripotency markers and exhibited capability to differentiate into the three germ layers in vitro.

DNA methylation changes in Down syndrome derived neural iPSCs uncover co-dysregulation of ZNF and HOX3 families of transcription factors.

Background: Down syndrome (DS) is characterized by neurodevelopmental abnormalities caused by partial or complete trisomy of human chromosome 21 (T21). Analysis of Down syndrome brain specimens has shown global epigenetic and transcriptional changes but their interplay during early neurogenesis remains largely unknown. We differentiated induced pluripotent stem cells (iPSCs) established from two DS patients with complete T21 and matched euploid donors into two distinct neural stages corresponding to early- and mid-gestational ages.

A VDAC1-Derived N-Terminal Peptide Inhibits Mutant SOD1-VDAC1 Interactions and Toxicity in the SOD1 Model of ALS.

Mutations in superoxide dismutase (SOD1) are the second most common cause of familial amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease caused by the death of motor neurons in the brain and spinal cord. SOD1 neurotoxicity has been attributed to aberrant accumulation of misfolded SOD1, which in its soluble form binds to intracellular organelles, such as mitochondria and ER, disrupting their functions. Here, we demonstrate that mutant SOD1 binds specifically to the N-terminal domain of the voltage-dependent anion channel (VDAC1), an outer mitochondrial membrane protein controlling cell energy, metabolic and survival pathways.

Transcriptome and Proteome Profiling of Neural Induced Pluripotent Stem Cells from Individuals with Down Syndrome Disclose Dynamic Dysregulations of Key Pathways and Cellular Functions.

Down syndrome (DS) or trisomy 21 (T21) is a leading genetic cause of intellectual disability. To gain insights into dynamics of molecular perturbations during neurogenesis in DS, we established a model using induced pluripotent stem cells (iPSC) with transcriptome profiles comparable to that of normal fetal brain development. When applied on iPSCs with T21, transcriptome and proteome signatures at two stages of differentiation revealed strong temporal dynamics of dysregulated genes, proteins and pathways belonging to 11 major functional clusters.

Boundary cap neural crest stem cell transplants contribute Mts1/S100A4-expressing cells in the glial scar.

Aim: During development, boundary cap neural crest stem cells (bNCSCs) assist sensory axon growth into the spinal cord. Here we repositioned them to test if they assist regeneration of sensory axons in adult mice after dorsal root avulsion injury.

Materials & Methods: Avulsed mice received bNCSC or human neural progenitor (hNP) cell transplants and their contributions to glial scar formation and sensory axon regeneration were analyzed with immunohistochemistry and transganglionic tracing.

A Combinatorial Approach to Induce Sensory Axon Regeneration into the Dorsal Root Avulsed Spinal Cord.

Spinal root injuries result in newly formed glial scar formation, which prevents regeneration of sensory axons causing permanent sensory loss. Previous studies showed that delivery of trophic factors or implantation of human neural progenitor cells supports sensory axon regeneration and partly restores sensory functions. In this study, we elucidate mechanisms underlying stem cell-mediated ingrowth of sensory axons after dorsal root avulsion (DRA).

Boundary Cap Neural Crest Stem Cells Promote Survival of Mutant SOD1 Motor Neurons.

ALS is a devastating disease resulting in degeneration of motor neurons (MNs) in the brain and spinal cord. The survival of MNs strongly depends on surrounding glial cells and neurotrophic support from muscles. We previously demonstrated that boundary cap neural crest stem cells (bNCSCs) can give rise to neurons and glial cells in vitro and in vivo and have multiple beneficial effects on co-cultured and co-implanted cells, including neural cells.

Human Embryonic Stem Cell-Derived Progenitors Assist Functional Sensory Axon Regeneration after Dorsal Root Avulsion Injury.

Dorsal root avulsion results in permanent impairment of sensory functions due to disconnection between the peripheral and central nervous system. Improved strategies are therefore needed to reconnect injured sensory neurons with their spinal cord targets in order to achieve functional repair after brachial and lumbosacral plexus avulsion injuries. Here, we show that sensory functions can be restored in the adult mouse if avulsed sensory fibers are bridged with the spinal cord by human neural progenitor (hNP) transplants.

Mover is a homomeric phospho-protein present on synaptic vesicles.

With remarkably few exceptions, the molecules mediating synaptic vesicle exocytosis at active zones are structurally and functionally conserved between vertebrates and invertebrates. Mover was found in a yeast-2-hybrid assay using the vertebrate-specific active zone scaffolding protein bassoon as a bait. Peptides of Mover have been reported in proteomics screens for self-interacting proteins, phosphorylated proteins, and synaptic vesicle proteins, respectively.